Criteria for Pediatric Sepsis

A Systematic Review and Meta-Analysis by the Pediatric Sepsis Definition Taskforce

Kusum Menon, MD, MSc; Luregn J. Schlapbach, MD, FCICM, PhD; Samuel Akech, MBChB, MMED, DPhil; Andrew Argent, MBBCh, MD(Paeds); Paolo Biban, MD; Enitan D. Carrol, MBChB, MD; Kathleen Chiotos, MD, MSCE; Mohammod Jobayer Chisti, MBBS, MMed, PhD; Idris V. R. Evans, MD, MSc; David P. Inwald, MB BChir, PhD; Paul Ishimine, MD; Niranjan Kissoon, MD; Rakesh Lodha, MD; Simon Nadel, MRCP; Cláudio Flauzino Oliveira, MD; Mark Peters, MBChB, PhD; Benham Sadeghirad, PharmD, MPH, PhD; Halden F. Scott, MD, MSCS; Daniela C. de Souza, MD; Pierre Tissieres, MD, DSc; R. Scott Watson, MD, MPH; Matthew O. Wiens, PharmD, PhD; James L. Wynn, MD; Jerry J. Zimmerman, MD, PhD; Lauren R. Sorce, RN, PhD

Disclosures

Crit Care Med. 2022;50(1):21-36. 

In This Article

Results

Overview of Included Studies

The search yielded 12,343 citations of which 969 underwent full-text review for eligibility. Of these, 863 were excluded (Figure 1); 106 citations, representing 35 countries, were retained for the systematic review and 81 articles (154,674 patients) provided sufficient data for the meta-analysis. The remaining 25 articles met the inclusion criteria but studied individual variables that were unable to be combined in the meta-analysis and were, therefore, described in the narrative review. Characteristics of all included studies are summarized in Table 1. Studies represented all regions from the World Bank economies[18] with 46.2% (47/106) being conducted in HICs, 30.2% (35/106) in UMICs, 22.6% (23/106) in LMICs, and one in a LIC. All multicenter studies except one[10] included sites from the same income level. The remaining study[10] was conducted in 23/26 HIC and 3/26 UMIC settings and was, therefore, classified as an HIC study. The patient characteristics for included studies are shown in Table 2. More than half the patients were male (pooled estimate 55.7%; 95% CI, 54.8–56.6). The majority of studies were of PICU patients (70.8%, 75/106) followed by those from the emergency department (ED) (10.4%, 11/106). The most commonly used definition of sepsis was the 2005 International Pediatric Sepsis Consensus Conference (2005 IPSCC) criteria (69.8%, 74/106; Supplementary Table 1, http://links.lww.com/CCM/G817).[3]

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram for included studies.

Included studies along with the variables assessed in the meta-analysis and narrative review are detailed in Supplementary Table 2 (http://links.lww.com/CCM/G818) and Supplementary Table 3 (http://links.lww.com/CCM/G819), respectively. Forest plots for variables with significant findings are shown in Supplementary Figure 1 (http://links.lww.com/CCM/G820), Supplementary Figure 2 (http://links.lww.com/CCM/G821), Supplementary Figure 3 (http://links.lww.com/CCM/G822), Supplementary Figure 4 (http://links.lww.com/CCM/G823), Supplementary Figure 5 (http://links.lww.com/CCM/G824), Supplementary Figure 6 (http://links.lww.com/CCM/G825), Supplementary Figure 7 (http://links.lww.com/CCM/G826), and Supplementary Figure 8 (http://links.lww.com/CCM/G827), and associations of these variables with the outcomes of sepsis and mortality are summarized in Table 3.

Variables Associated With Sepsis, Severe Sepsis, Septic Shock in Children With Suspected Infection

Sixteen studies on 9,629 patients provided data for the meta-analysis assessing the association of 16 variables among children with suspected infection with the outcome of sepsis, severe sepsis, or septic shock (for study and patient characteristics, see Supplementary Table 4, http://links.lww.com/CCM/G828; and Supplementary Table 1, http://links.lww.com/CCM/G817). Sepsis and severe sepsis among infected children were associated with decreased level of consciousness[24–27] and higher Pediatric Risk of Mortality (PRISM) scores,[28,29] respectively (Supplementary Figure 2, http://links.lww.com/CCM/G821; and Supplementary Figure 8, http://links.lww.com/CCM/G827). Our meta-analysis did not demonstrate an association among age, age groups, gender or malnutrition,[30–34] and sepsis, severe sepsis, or septic shock (Supplementary Table 5, http://links.lww.com/CCM/G829). Sepsis among infected children was not associated with pooled estimates of haemoglobin,[35–37] C-reactive protein (CRP),[25,27] or procalcitonin.[38,39]

Variables Associated With NPMODS and Mortality in Children With Sepsis, Severe Sepsis, or Septic Shock

Mortality rates for sepsis, severe sepsis, and/or septic shock were provided in 86 of 106 included studies. The pooled mortality rate using a random-effects model for patients with sepsis was 10.9% (n = 47 studies; 95% CI, 8.9–13.2), for severe sepsis was 23.0% (n = 26 studies; 95% CI, 19.6–26.9), and for septic shock was 36.8% (n = 28 studies; 95% CI, 29.4–44.9). The pooled mortality rates varied among HIC, UMIC, and LMIC locations for each of sepsis, severe sepsis, and septic shock patient groups (p < 0.0001) (Figure 2). The mortality analysis did not include LICs as there was only one study with eligible data.

Figure 2.

Pooled mortality rates for sepsis, severe sepsis, and septic shock in included studies across World Bank Income classifications. HIC = high-income country, LMIC = low-middle-income country, UMIC = upper-middle-income country.

Sixty-nine studies on 145,461 patients provided data for the meta-analysis of the association of 54 variables with the primary outcome of mortality (for patient and study characteristics, see Supplementary Table 1, http://links.lww.com/CCM/G817; and Supplementary Table 4, http://links.lww.com/CCM/G828, respectively). One study reported separately on two populations that were, therefore, reported as two studies in the meta-analysis.[23] Only one study reported NPMODS as an outcome, and two reported a composite outcome of NPMODS and death. Meta-analysis with NPMODS as the outcome was not possible as none of these studies assessed the same variables.

Pooled estimates supported an increased odds of mortality in patients with severe acute malnutrition,[31,40,41] chronic conditions,[31,33,42–50] and oncologic conditions[23,31,47,51–54] (Supplementary Figure 1, http://links.lww.com/CCM/G820). The evidence did not support an association between age, age groups, or gender with mortality. In addition, no association was noted between, obesity[55–57] or malnutrition[30–34] and mortality, but only a small number of studies assessed these variables.

Clinical Variables

Among children with sepsis, severe sepsis, and septic shock, pooled estimates provide strong support for increased mortality with hypotension,[46,47,58,59] use of vasoactive agents/inotropes,[26,31–33,40,41,44,49,50,58,60–69] increased vasoactive-inotropic score (VIS),[51,53,68,70–72] increased shock index,[58,73,74] decreased level of consciousness,[58,59,67] decreased Glasgow Coma Scale (GCS),[53,70,75] and mechanical ventilation[26,28,31,32,40–44,46,49–51,53,58–62,65–69,71,72,75–80] (Supplementary Figure 2, http://links.lww.com/CCM/G821). There were no mortality differences significantly associated with heart rate,[47,53,58,71,74,76] mean blood pressure,[53,71] systolic blood pressure,[47,58,67,74,76] central venous pressures,[51,53,71] and arterial oxygen saturations.[47,58]

Laboratory Variables

Pooled estimates provide strong support for a difference in the following laboratory measures between nonsurvivors and survivors: lower serum pH,[53,58,72,75] higher lactate,[43,50,51,53,60–62,65,68,71,72,74–76,81–83] higher serum base deficit,[62,71,75,76,84,85] higher urea,[58,76,81,86] higher creatinine,[53,58,71,76,81,83,85,86] lower platelet count,[41,43,50,53,58,62,71,77,81,83–85,87,88] lower fibrinogen,[62,81,84,85,87] higher potassium,[62,71,76] lower albumin,[53,76,83] higher procalcitonin,[26,35,43,76,83,85,89–91] and higher alanine aminotransferase (ALT)[58,76,81] (Supplementary Figure 3, http://links.lww.com/CCM/G822; Supplementary Figure 4, http://links.lww.com/CCM/G823; Supplementary Figure 5, http://links.lww.com/CCM/G824; and Supplementary Figure 6, http://links.lww.com/CCM/G825). Pooled estimates did not support a difference between nonsurvivors and survivors in mean glucose,[50,68,71,72,76] total bilirubin,[53,58,76,81,85,86] WBC,[26,43,50,53,58,62,71,75–77,81,83,85,87,89] haemoglobin,[26,43,50,71,83,85] international normalized ratio,[62,81] prothrombin time,[53,71,76,81,92] activated partial thromboplastin time,[62,71,81,92] and brain natriuretic peptide.[51,66,76]

Organ Dysfunction Measures and Illness Severity Scores

Our meta-analysis provides strong support for greater organ dysfunction in nonsurvivors compared with survivors as shown by the pooled estimates for renal dysfunction,[50,64,67,70] multi-organ dysfunction (MODS),[23,33,41,50,69,70,93,94] number of organ dysfunctions,[28,40,64,83] PEdiatric Logistic Organ Dysfunction (PELOD) score,[23,28,40,44,50,53,55,60,65,72,85] and PELOD-2.[85,86,95] Our meta-analysis also provides strong support for greater illness severity in nonsurvivors compared with survivors as shown by the pooled estimates pediatric Sequential (Sepsis-related) Organ Failure Assessment (pSOFA)[50,58,70,95] and Sequential (Sepsis-related) Organ Failure Assessment (SOFA),[85,86,95] PRISM,[32,43,51,53,55,60–62,64,68,70–72,75,77,81,84,85,88] Pediatric Index of Mortality (PIM)-2,[79,85] and PIM-3[23,61,65,85] (Supplementary Figure 7, http://links.lww.com/CCM/G826; and Supplementary Figure 8, http://links.lww.com/CCM/G827).

Narrative Review of n = 25 Studies

Three studies reported risk factors for developing sepsis or septic shock among children with infection. Two studies reported differing thresholds of CRP (81.9 and 154.3 nmol/dL) and procalcitonin levels (43 and 19.1 ng/mL) for association with septic shock in patients with meningococcemia[96] and sepsis,[97] respectively. One study of children presenting to the ED with suspected infection found that a lactate level of greater than 3 mmol/L was associated with higher risk of sepsis.[98]

In one study of patients with septic shock, those with hematopoietic cell transplants had increased odds of mortality (OR 4.74; 95% CI, 2.56–8.77),[99] and those with progressively higher Logistic Organ Dysfunction Score and alert, verbal, pain, unresponsive score demonstrated increasing positive predictive values for early mortality from 40% to 60% and 39.3% to 50%, respectively.[100] Several studies assessed cardiovascular variables. In one study, the Tp-e interval/QT on an electrocardiogram was an independent predictor of mortality in patients with septic shock.[101] A VIS of greater than 20 was associated with increased mortality.[102] Another study suggested time-dependant cutoffs for shock index values from 0- to 6-hour postadmission,[103] and two studies each found an association of a decreased left ventricular ejection fraction (45% and 55%) with mortality.[104,105]

Laboratory values that showed an association with mortality in single studies included red cell distribution width elevation;[106] antithrombin III levels below 41.5% (< 1 yr old) and 67.5% (≥ 1 yr old);[92] 25-hydroxy vitamin D less than 50 nmol/L;[107] baseline cortisol cutoff of 20 μg/dL and postadrenocorticotropic hormone stimulation level of less than or equal to 9 μg/dL;[108] lower serum zinc levels;[109] lower high-density lipoprotein, low-density lipoprotein, and cholesterol levels;[110] and lower total T3 and T4, and free T3 and T4 hormone levels.[111] Two studies assessed serum troponin in sepsis with one reporting an association of serum troponin greater than 1 ng/dL with mortality,[112] whereas the other found higher levels of troponin in nonsurvivors compared with survivors.[71] Serum lactate levels were studied using three criteria. Serum-lactate-to-albumin ratio greater than 1.17 was associated with increased mortality,[113] and lack of lactate clearance (decrease of ≤ 10%) or normalization (< 2 mmol/L) was associated with persistent MODS.[114]

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